1. Field of the Invention
The present invention relates to compositions and methods for the topical administration of pharmaceutically active agents to a mammal in need thereof. More particularly, the present invention relates to anesthesia and local anesthetic agents for topical administration. Still more particularly, the invention relates to a method for the topical administration of an anesthetic agent or a combination of anesthetic agents to prevent or ameliorate pain.
There is no limitation on the type of pharmaceutical agent that can be used in the present invention, provided that it can be absorbed topically, typically percutaneously. Thus, the pharmaceutical agent includes both drugs that are topically applied for local effects and those which can be administered topically for systemic effects.
2. Description of Background Art
Anesthetic agents are pharmacologically active agents that block nerve conduction when applied in therapeutically effective amounts. They can be used for local or systemic application. Anesthetic agents have been used extensively in the medical field to obtain topical anesthesia. The term "topical" or "topically" is used here in its coventional sense as referring to a spot, which can be in or on any part of the body, including but not limited to the epidermis, any other dermis, or any other body tissue. Topical administration or application means the direct contact of the anesthetic with tissue, such as skin or membrane, particularly the oral or buccal mucosa. Topical administration also includes application to hardened tissue such as teeth and appendages of the skin such as nails and hair. Previous methods of applying topical anesthetic agents to the skin or mucosa have used "non-finite" or liquid or semi-liquid carriers such as gels, lotions, emulsions, creams, plasters, or ointments, or "finite" carriers, non-spreading substances which retain their form, e.g. patches, dressings and bandages.
Local anesthetics generally are esters or amides of benzoic acid derivatives, administered either as the free base or the acid-addition salt. Free bases tend to be irritating at high concentrations. Acid-addition salts have low skin permeability.
To be effective, a topical, local anesthetic should contain sufficient concentration of the active agent to produce an anesthetic effect, it should penetrate the tissue such as intact skin or mucosa sufficiently to deliver a therapeutic dose, and it should exhibit rapid onset of anesthetic action and have a prolonged anesthetic effect. In achieving the foregoing, it is often desirable to have the anesthetic agent present in a high concentration to effect a rapid onset and, additionally or alternatively, in excess of the amount that can be immediately absorbed through the dermis at the site of application, so as to prolong anesthesia. On the other hand, the presence of the anesthetic agent primarily in crystalline form may irritate sensitive tissues such as mucosal tissues. This is particularly true with regard to lidocaine.
A number of references disclose local anesthetic compositions. For instance, Swedish Patent Publication No. 352,239 published Dec. 27, 1972 in the name of S. G. Davis et al., assigned to Astra Pharmaceutical Products, Inc., and based on Swedish patent application No. 17744/70 filed Dec. 30, 1970, discloses a local anesthetic film containing up to 50% lidocaine in crystallized, microdispersed form. In its final form, this composition lacks a solvent for the anesthetic agent. The preparation is prepared by adding a solution of lidocaine in an organic solvent or an acid addition salt in water, under heat and agitation, to a solution or suspension of a film-forming material, namely carboxymethyl cellulose, polyvinyl alcohol, or a mixture of polyvinyl alcohol and polyvinyl pyrrolidone in water, followed by heating to remove any solvent present.
U.S. Pat. No. 4,937,078 to Mezei, et al. describes a liposome encapsulated local anesthetic or analgesic agent that is said to provide, when applied to the skin or mucous membrane, greater local anesthesia and analgesia than the same agents incorporated in conventional vehicles such as ointments, creams, or lotions. These liposomal films are preferably applied under occlusion.
U.S. Pat. Nos. 4,572,832 and 4,695,465 to Kigasawa and 3,249,109 to Maeth all describe the use of water soluble protein based systems which incorporate anesthetics, and which also contain a tackifier and a polyhydric alcohol solvent. In the compositions of these references, the water soluble protein gives the base its consistency and bulk and serves as an essential vehicle for the incorporation of medicaments and therapeutic agents.
U.S. Pat. No. 4,894,232 to Reul, et al. discloses a base for mucosal or denture adhesive pastes and a process for the preparation thereof. Lidocaine is one possible therapeutic agent suitable for this paste.
U.S. Pat. No. 3,814,095 to Lubens describes an absorbent pad for topical application of an anesthetic agent and having a peripheral adhesive.
It is also known to combine two local anesthetic free bases with different melting points. By mixing the two anesthetic bases, an eutectic mixture has been reported that is liquid at room temperature, making it possible to attain higher concentrations of the active bases.
U.S. Pat. No. 4,888,354 by Chang relates to a combination of the free base and an acid addition salt of a variety of drugs, typically in a liquid carrier, to increase skin penetration rates. Anesthetics, along with a list of other suitable drugs are mentioned. This reference specifically teaches that base and acid-addition forms of the same drug be used in carrier.
U.S. Pat. No. 2,352,691 to Curtis teaches the use of salicylate salts of alkamine esters of amino benzoic acid to enhance the water solubility of anesthetic agents. The salt form predominates over any base form. In one example, this reference discloses a solution of procaine acetyl salicylate containing insoluble anesthetics such as benzocaine, butesin, orthoform, or their salts, in certain glycols which are combined with a volatile solvent, and then used to saturate gauze bandages or other suitable fabrics.
U.S. Pat. No. 2,142,537 to Tisza describes an ointment containing isoamylhydrocupreine in combination with a quick acting local anesthetic to overcome the undesirable irritation caused by the prolonged acting anesthetic isoamylhydrocupreine or its salts. The preparation of Tisza combines short and long acting anesthetic agents. However, such preparation is not provided in a convenient form for topical administration, nor does it appear to contain a high concentration of finely-dispersed drug.
U.S. Pat. No. 4,900,552 by Sanvordeker et al. discloses a trilaminate film suitable for prolonged and sustained delivery of an active ingredient in a buccal cavity. Specifically a hydratable mucoadhesive base layer, a non-adhesive reservoir layer and a water-impermeable carrier film sandwiched between and bonded to the base layer and the reservoir layer form the trilaminate film. This reference generally describes and claims the addition of an active ingredient to the non-adhesive reservoir layer.
U.S. Pat. No. 2,277,038 to Curtis relates to preparations containing a mixture of two or more anesthetic agent salts having different pH values in solution, whereby the pH value of the combined mixture in solution may be adjusted to obtain a higher degree of stability of the solution, and at relatively higher pH, a more rapid onset of anesthetic action. The anesthetic agents in Curtis are not in highly dispersed form and are used in a liquid-soaked fabric.
Procaine salts of different drugs, namely procaine penicillin G, given by intramuscular injection are also known to prolong the antimicrobial action of the antibiotic.
Commonly, prolongation of anesthesia with topical anesthetics has been achieved by the addition of vasoconstrictors, such as the catecholamine, epinephrine, which caused constriction of blood vessels. Since catecholamines are not particularly effective when applied topically, such a prolongation is of minimal usefulness for topical anesthetics. The primary drawbacks of this approach are the potential adverse side effects of catecholamines, and the prolongation itself.
Although many local anesthetic compositions have been proposed, it has been discovered that the incorporation of one or more anesthetic agents in a solvent for the anesthetic agent into a flexible, finite, pharmaceutically acceptable carrier, permits an exceptionally high loading of anesthetic agent in the carrier, permitting more rapid delivery of the anesthetic agent to the tissue such as the dermal membrane without substantive crystallization of the anesthetic agent which can limit absorption by the skin and which can cause irritation of the skin or other dermal membrane or tissue.
It has surprisingly been found that concentrations of substantially dissolved anesthetic agent as high as 50% by weight can be achieved in a system in which the adhesion of the adhesive carrier is not hindered. Prolongation of anesthesia can thus be achieved by increasing the amount of time the composition is applied, without detrimental irritation. The compositions of the present invention are in convenient form for topical application of the anesthetic agents, thereby enabling such anesthetics to penetrate the dermis, for example, intact skin or a mucous membrane. Moreover, the anesthetic action is highly localized. Because the drug is substantially microdispersed in the carrier, it is more readily available for permeation into the tissue, e.g. the skin or dermal membrane.
It still further has surprisingly been found that the use of two different local anesthetic agents, the first in base form and the second in salt form, in a pharmaceutically acceptable carrier in a finite or non-finite form, including a non-aqueous solvent for the anesthetic agents, permits the attainment of high anesthetic agent concentrations in the final product, for example of up to 50% by weight in microdispersed form, without crystallization of the anesthetic agents which can cause irritation of the skin or other dermal membrane or other tissue.
Thus, in one embodiment, the present invention is in convenient form for topical application of the anesthetic agents, thereby enabling such anesthetics to penetrate tissue such as intact skin, skin appendages or mucous membranes and have a highly localized effect. Furthermore, the combination of the salt and base forms, advantageously results in rapid onset of anesthetic action with prolonged anesthetic effect.